Nitrogen dioxide storage device

ABSTRACT

A nitric oxide delivery system can include a cassette which is a single use disposable component used to store liquid N 2 O 4 , activate upon operator demand, convert N 2 O 4  to NO 2  via a heating element(s) controlled by a console to deliver NO 2  at a controlled flow rate, direct concentrated NO 2  to a contained pair of conversion cartridges and exhaust NO gas to the console for delivery to the patient.

CLAIM FOR PRIORITY

This application is a divisional of U.S. application Ser. No.14/918,511, filed Oct. 20, 2015, now U.S. Pat. No. 10,213,572, whichclaims priority under 35 U.S.C. § 119(e) to U.S. patent application Ser.No. 62/066,345 filed on Oct. 20, 2014, each of which is herebyincorporated by reference in its entirety.

TECHNICAL FIELD

The invention relates to systems and methods for the storage anddelivery of a gas including at least 1% nitric oxide.

BACKGROUND

Some disorders or physiological conditions can be mediated by inhalationof nitric oxide. The use of low concentrations of inhaled nitric oxidecan prevent, reverse, or limit the progression of disorders which caninclude, but are not limited to, acute pulmonary vasoconstriction,traumatic injury, aspiration or inhalation injury, fat embolism in thelung, acidosis, inflammation of the lung, adult respiratory distresssyndrome, acute pulmonary edema, acute mountain sickness, post cardiacsurgery acute pulmonary hypertension, persistent pulmonary hypertensionof a newborn, perinatal aspiration syndrome, haline membrane disease,acute pulmonary thromboembolism, heparin-protamine reactions, sepsis,asthma and status asthmaticus or hypoxia. Nitric oxide can also be usedto treat chronic pulmonary hypertension, bronchopulmonary dysplasia,chronic pulmonary thromboembolism and idiopathic or primary pulmonaryhypertension or chronic hypoxia.

Generally, nitric oxide can be inhaled or otherwise delivered to theindividual's lungs. Providing a therapeutic dose of NO could treat apatient suffering from a disorder or physiological condition that can bemediated by inhalation of NO or supplement or minimize the need fortraditional treatments in such disorders or physiological conditions.Typically, the NO gas can be supplied in a bottled gaseous form dilutedin nitrogen gas (N₂). Great care should be taken to prevent the presenceof even trace amounts of oxygen (O₂) in the tank of NO gas because theNO, in the presence of O₂, can be oxidized to nitrogen dioxide (NO₂).Unlike NO, the part per million levels of NO₂ gas can be highly toxic ifinhaled and can form nitric and nitrous acid in the lungs.

SUMMARY

In general, a cassette for conversion of nitrogen dioxide to nitricoxide can include a sealed housing, a first cartridge capable ofconverting nitrogen dioxide gas to nitric oxide within the sealedhousing, the first cartridge comprising an inlet, a diverter, a body, anoutlet, and a porous solid matrix including a reducing agent, the poroussolid matrix being positioned within the first cartridge such that thereis a space between the body of the first cartridge and the porous solidmatrix, wherein the porous solid matrix includes an open passageparallel to the length of the body of the first cartridge, a secondcartridge capable of converting nitrogen dioxide gas to nitric oxide,wherein an outlet of the first cartridge and an inlet of the secondcartridge is connected, the second cartridge comprising an inlet, adiverter, a body, an outlet, and a porous solid matrix including areducing agent, the porous solid matrix being positioned within thefirst cartridge such that there is a space between the body of the firstcartridge and the porous solid matrix, wherein the porous solid matrixincludes an open passage parallel to the length of the body of the firstcartridge; and an inerting chamber including an inerting material.

In certain embodiments, the space has a width, which is a distancebetween the surface of the porous solid matrix to the receptacle, andthe width of the space is variable along the length of the receptacle,and wherein the inlet is configured to receive a gas flow, the diverterdirects the gas flow to the space between the body and the porous solidmatrix, and the gas flow is fluidly communicated to the outlet throughthe porous solid matrix to convert nitrogen dioxide in the gas flow intonitric oxide.

In other embodiments, the width of the space decreases along a portionof the length of the receptacle.

In other embodiments, the width of the space increases along a portionof the length of the receptacle.

In other embodiments, the width of the space increases along a portionof the length of the receptacle extending from the inlet toapproximately the midpoint of the receptacle, and the width of the spacedecreases along a portion of the length of the receptacle extending fromthe approximately the midpoint of the receptacle to the outlet.

In other embodiments, the sealed housing further comprises a storagedevice of N₂O₄ and NO₂.

In other embodiments, the storage device is contained within a shuttletube, wherein the tube stabilizes the storage device.

In other embodiments, the shuttle tube is positioned such that theinerting chamber opens to the storage device during shipment.

In other embodiments, the inerting material undergoes a permanent colorchange when the storage device is broken.

In other embodiments, the sealed housing further comprises a restrictor.

In other embodiments, the restrictor connects the storage device and thefirst cartridge.

In other embodiments, the sealed housing further comprises a heater.

In other embodiments, the heater wraps around the storage device andcontrols an output of nitrogen dioxide gas by changing the temperatureof the storage device.

In other embodiments, the cassette is disposable after single use.

In other embodiments, the cassette is further connected to a console,wherein the console controls the heater.

In general, a storage device of liquid nitrogen dioxide can include avessel including an ampoule, an ampoule including liquid nitrogendioxide, wherein the liquid nitrogen dioxide converts to nitric oxidewhen the ampoule is broken, a restrictor, wherein a proximal end of therestrictor is facing the ampoule and a distal end of the restrictorprovides an exit for nitric oxide gas; a leak valve connected to theampoule; and a shuttle tube containing the ampoule.

In certain embodiments, the shuttle tube connects with the restrictorwhen a user breaks the ampoule.

In other embodiments, the storage device is further connected to aheater.

In other embodiments, the heater is activated when a user breaks theampoule.

In other embodiments, the storage device is further connected to aninert chamber through the leak valve.

In other embodiments, the shuttle rotates to connect the ampoule eitherto the inert chamber or to the restrictor.

In other embodiments, the storage devices is further connected to amixing T-fitting.

In other embodiments, an air flows into the mixing T-fitting.

In other embodiments, the volume of the storage device is not greaterthan 0.53 mL.

In other embodiments, the storage is device is contained in a sealedhousing.

In other embodiments, the sealed housing further includes a firstcartridge capable of converting nitrogen dioxide gas to nitric oxidewithin the sealed housing, the first cartridge comprising an inlet, adiverter, a body, an outlet, and a porous solid matrix including areducing agent, the porous solid matrix being positioned within thefirst cartridge such that there is a space between the body of the firstcartridge and the porous solid matrix, wherein the porous solid matrixincludes an open passage parallel to the length of the body of the firstcartridge, a second cartridge capable of converting nitrogen dioxide gasto nitric oxide, wherein an outlet of the first cartridge and an inletof the second cartridge is connected, the second cartridge comprising aninlet, a diverter, a body, an outlet, and a porous solid matrixincluding a reducing agent, the porous solid matrix being positionedwithin the first cartridge such that there is a space between the bodyof the first cartridge and the porous solid matrix, wherein the poroussolid matrix includes an open passage parallel to the length of the bodyof the first cartridge; and an inerting chamber including an inertingmaterial.

In other embodiments, the space has a width, which is a distance betweenthe surface of the porous solid matrix to the receptacle, and the widthof the space is variable along the length of the receptacle, and whereinthe inlet is configured to receive a gas flow, the diverter directs thegas flow to the space between the body and the porous solid matrix, andthe gas flow is fluidly communicated to the outlet through the poroussolid matrix to convert nitrogen dioxide in the gas flow into nitricoxide.

In other embodiments, the width of the space decreases along a portionof the length of the receptacle.

In other embodiments, the width of the space increases along a portionof the length of the receptacle.

In other embodiments, the width of the space increases along a portionof the length of the receptacle extending from the inlet toapproximately the midpoint of the receptacle, and the width of the spacedecreases along a portion of the length of the receptacle extending fromthe approximately the midpoint of the receptacle to the outlet.

Other aspects, embodiments, and features can be apparent from thefollowing description, the drawings, and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a drawing depicting a conventional nitric oxide deliveryplatform.

FIG. 2 is a drawing depicting a nitric oxide delivery platform.

FIGS. 3A-3D are schematic drawings depicting the supply subassembly.

FIG. 4 is a schematic depicting a Schrader-type valve.

FIG. 5A is a schematic depicting a cartridge.

FIG. 5B is a cross-section of FIG. 5A.

FIG. 6 is a schematic depicting a liquid module.

FIG. 7 is a flow diagram of supply subassembly

FIG. 8 is an exemplary console.

FIG. 9 depicts an exemplary console.

FIG. 10 shows an exemplary output performance curve.

FIG. 11 shows a cassette.

FIG. 12 shows a cassette assembly.

FIG. 13 shows a liquid vessel and restrictor assembly.

FIG. 14 depicts cartridge components.

FIG. 15 shows cartridges in an assembly.

FIG. 16 shows a cartridge mounted on a base.

FIG. 17 shows a cassette base manifold.

FIG. 18A shows a gas flow bath showing the exit locations on the base.

FIG. 18B shows the exit locations from FIG. 18A.

FIG. 19 shows a cross-section of a Schrader-like valve.

FIG. 20 shows an exemplary cassette packaging.

FIG. 21 shows a cassette base assembly.

FIG. 22-26 shows an exemplary shuttle mechanism in variousconfigurations

FIG. 27 shows an exemplary patient flow port liquid vessel/restrictorhousing assembly.

FIG. 28 shows a restrictor housing tee fitting assembly.

FIG. 29 shows a liquid module housing and base housing.

FIG. 30 shows a cassette cross-section through the inerting chamber andpurge chamber.

FIG. 31 depicts a cassette assembly.

FIG. 32 shows a cross-section of a cassette through cartridges.

FIG. 33 shows a cross-section of a cassette.

DETAILED DESCRIPTION

When delivering nitric oxide (NO) for therapeutic use to a mammal, itcan be important to avoid delivery of nitrogen dioxide (NO₂) to themammal. Nitrogen dioxide (NO₂) can be formed by the oxidation of nitricoxide (NO) with oxygen (O₂). The rate of formation of nitrogen dioxide(NO₂) can be proportional to the oxygen (O₂) concentration multiplied bythe square of the nitric oxide (NO) concentration. A NO delivery systemcan convert nitrogen dioxide (NO₂) to nitric oxide (NO). Additionally,nitric oxide can form nitrogen dioxide at increased concentrations.

Referring to FIG. 1, platforms for delivering nitric oxide currentlyexist. For example, the standard platform in use can include a gasbottle 100 which contains 800 ppm NO in nitrogen (N₂) (FIG. 1). Thenitric oxide/nitrogen gas can be released from the gas bottle 100 andthe pressure and rate of the gas can be controlled using a gas regulator105 and/or a valve 110. Using a gas bottle platform, the NO output 115can be defined by the nitrogen dioxide concentration in the gas bottle100 and cannot be varied by the user. For example, if the gas bottlecontained 80 ppm of NO₂ in air or oxygen, then the output can be 80 ppmof NO₂ in air or oxygen. The gas can be supplied, typically, at apressure of 2000 psi or greater. Typically, a gas bottle includes atleast 99.9% N₂. A gas bottle platform can work well, but can be large,heavy and cumbersome because the platform can include a heavy aluminumor steel gas pressure cylinder, a gas regulator and a flow controller.

Examples of commercially available platforms are manufactured by Ikaria,two of which are the INOvent and the INOmax DS. Both of these systemsuse gas bottles of NO diluted in nitrogen (N₂), which is then mixed withoxygen enriched air to provide the inhaled NO gas. Both of these systemsare designed to work with a ventilator in an intensive care setting in ahospital. These platforms are not suitable for ambulatory or home use.

Referring to FIG. 2, as another example, a platform can be a standalonegas bottle platform. A gas bottle platform 200 can include a gas bottle205, a gas regulator 210 and a GeNO cartridge 215. The output from thegas cylinder can be delivered to a GeNO cartridge, where one of theoxygen atoms in the NO₂ is stripped out by a reducing agent, forexample, ascorbic acid, to generate ultra pure NO. The GeNO cartridge isdescribed in greater detail below and in U.S. patent application Ser.Nos. 12/500,929, 12/541,144, 12/619,959 and 12/951,811, and U.S. Pat.No. 7,560,076, each of which is incorporated by reference in itsentirety. This platform has been cleared by FDA for use in two clinicaltrials with human patients.

Another variation for delivering NO can be to start with a NO₂ gasconcentration of up to 2,000 ppm in air or oxygen and dilute it down to80 ppm of NO₂. This set up can be even more complex in that it canrequire precision mass flow controllers and meters in order to get astable mixing ratio.

As mentioned above, the disadvantage of the gas bottle platform can bethat the platform can be large and heavy. The platform can also beinconvenient to use for chronic treatment as an ambulatory platform. Gasbottles can also be cumbersome when used in a confined space such as inan Intensive Care Unit, in a hospital or in a home. In addition, the gasbottles need to be tied down to prevent them from falling over andcausing physical injury. Also, the regulator can break off in a fall,and the sudden venting of gas through the opening can cause the heavybottle to become a projectile, which can penetrate numerous walls andcause injury or death. Therefore, there is a need for a nitric oxidedelivery platform, which can includes a nitric oxide source which issmall and portable for use in an ambulatory or home setting.

A cassette can be a fully integrated single use disposable componentwhich can store liquid N₂O₄, activate (break glass ampoule) uponoperator demand, convert N₂O₄ to NO₂ via a heating element(s) controlledby a console to deliver NO₂ at a controlled flow rate, directconcentrated NO₂ to a contained pair of conversion cartridges andexhaust NO gas to the console for delivery to the patient.

Referring to FIGS. 3A to 3D, FIG. 3A is a schematic of a cassette whichincludes two primary cartridges 301, a liquid module 302 containing theN₂O₄ ampule and shuttle mechanism, and a restrictor column assembly 303.In FIG. 3B, an inerting chamber 304 connects two primary cartridges. Acover 306 is clear to be able to see the color change of a neutralizedmaterial. Heater and thermistor contacts 305 are at the opposite end ofthe cover. FIG. 3C shows the cassette base 310 with access ports. Theaccess ports are covers with a foil seal before usage. FIG. 3D shows thelayout of the cassette base including a purge inlet 312, a purge outlet313, an air inlet 314, a first primary cartridge inlet 315, a secondprimary cartridge inlet 316, and a restrictor “T” 317.

Cassette Integrated Safety Features

A cassette can provide safety elements to restrict and convert NO andNO₂ gas from discharge into the atmosphere. A liquid module can provideadequate safety features to limit NO₂ exposure to the equipment user orshipping carrier.

A cassette can contain the following protections for shippers and usersfrom exposure to NO₂ gas exposure:

Glass Ampule—SAFETY #1

N₂O₄ can be contained in the liquid form and housed in a glass vial. Themaximum volume N₂O₄ contained within the glass ampule can be 0.53 mlwhich is below the EPA limit should a catastrophic failure occur(inadvertent human exposure—established for catastrophic failure of anNO₂ gas cylinder). Environmental exposure of liquid N₂O₄ can diffuseinto a room at a slow rate as the gas much heat up to convert into NO₂as compared to a broken NO₂ gas regulator with contents under highpressure and immediate discharge into the room. The glass ampule can besecured to the shuttle with a Teflon shrink tube. This shrink tube canoffer a number of benefits: a) stabilize the glass ampule duringshipping and dampen vibration; b) provide a glass shard containmentbarrier.

Shuttle Seals—SAFETY #2A&B and #3A&B

A glass ampule can be contained within a two position component thatenables glass breakage and shuttles a seal to either end (output orinerting) of the liquid vessel—each end containing a different function.A dual leak-tight safety seal is fastened to both ends of the Shuttle.The inerting seal can control gas flow to the inerting chamber of theliquid module. The output seal controls gas flow to the patient. TheShuttle is manually positioned to direct gas flow to the inerting or theoutput side. The seals are designed to provide redundancy by combiningboth a radial seal and a luer seal mating to a polished exhaust port.

Inerting Chamber—SAFETY #4

The shuttle mechanism can be positioned with the inerting chamber opento the liquid vessel during product shipment. Should the glass ampulebreak in transit, the entire contents of the liquid vessel can bedirected to the neutralizing material to make the NO₂ gas inactivethrough chemical reaction. This provides an additional safety means tothe cassette. In addition, the inerting material can undergo a permanentcolor change, visible through the cassette window, to provide the userwith an indication that the cassette is no longer functional and shouldnot be utilized.

Slow Leak Valve—SAFETY #5

The product can be shipped with the inerting seal in the OPEN positionsuch that there is direct communication between the liquid chamber andthe inerting material. Should the glass vial break in transit, the NO₂gas can be directed to the inerting material to be neutralized. The gasflow rate into the inerting chamber can be controlled such to managereaction temperature build-up and provide adequate time for the inertingreaction to occur.

The slow leak valve can provide an additional safety feature of reducingthe rate of NO₂ gas discharge to the environment should a catastrophicfailure occur.

Schrader-type Valves (FIG. 4)—SAFETY #6A&B

At the base of the cassette can be three access ports (as well as DCpowered heater connectors): a room air pump inflow, a NO gas outflow, apurge inflow. All high concentration NO₂ gas plumbing is containedwithin the cassette, reducing the environmental exposure from a leak.

Referring to FIG. 4, both the air inflow and NO gas outflow ports canprovide redundant seals independent from the liquid vessel shuttlemechanism in case of an outlet seal failure. These seals can beactivated after insertion of the cassette into the console and uponsystem activation to insert the air pump inlet and NO gas outlet probesinto the cassette. The Schrader-type seals are normally closed springloaded and are mechanically displaced upon introduction of the probesfrom the console. Upon removal of the probes from the cassette, theschrader seals are automatically returned to the sealing positions. FIG.4 shows schrader valve 401, console access 402, a foil seal 403, andspring(s) 404.

Tamper-Proof Seals—SAFETY #7 & #8

The base of the cassette can contain a foil seal covering the room airpump inflow and NO gas outflow ports. This seal can be punctured uponsystem activation (probe insertion into the cassette) and provide atamper evident seal from the user inadvertently challenging the SchraderSeals.

The top of the cassette can contain a foil or paper seal to cover thecassette activation rotation knob. This rotation knob engages theconsole for activation of the glass vial breakage.

Purge Material—SAFETY #9

The cassette can contain a purge material which is used to scrub NO gasemerging from the console during system priming to eliminate air fromthe console lines and cassette components. This purge can be directed tothe cassette purge material.

Cassette Construction—Safety #10

The liquid module can be hermetically welded aluminum and capable ofwithstanding internal pressures to 100 psi. All liquid module seals canbe compatible with N₂O₄ or high concentration NO₂ gas and withstandtemperatures to 70° C.

Cassette Packaging—Safety #11

The cassette can be initially packaged in a foil pouch as a safety andmoisture barrier. Stability testing can be conducted to determine thelong term need for this pouch.

Cassette Sub-Assemblies and Features

The cassette can be designed such the sub-assemblies are not positionalorientation sensitive so as not to restrict cassette positioning withinthe console or provide transportability limitations.

Liquid Module Sub Assembly

A liquid module is a self-contained subassembly that houses the N₂O₄liquid and associated integrated safeties and controls associated withthe NO₂ gas delivery. The liquid module is initially configured such tomaintain communication between the liquid vessel and the inertingchamber should a glass vial failure occur and N₂O₄/NO₂ fill the liquidvessel.

A liquid vessel can interface the cassette distribution manifold in agas-tight assembly. The concentrated NO₂ gas flow emanating from theoutput of the liquid vessel and restrictor flow column can dischargeinto the room air pump inflow and be carried to the first primarycartridge.

The liquid module can be positioned in the cassette and on thedistribution manifold such to align the activation cam in its initialposition to receive the console activation knob.

A liquid vessel can be wrapped with DC electrical flexible heaterspositioned about the liquid vessel and the restrictor column segment. Atemperature console can control the temperature of the liquid/gas suchto generate the programmed milligrams/deciliter (mg/dl) delivered to thepatient line.

Cartridge Sub-Assembly

A primary cartridge can provide the means to convert NO₂ to NO gasthrough a reaction with ascorbic acid pretreated on the surfaces of thehigh density polyethylene and silica gel composite matrix. The cartridgeshould be capable of converting the contents of one liquid vial of N₂O₄to NO gas. The cassette can contain two primary cartridges. The primarycartridges can come from two separate lots of production to provide aredundant NO₂ conversion should a “bad” of cartridges occur. The primarycartridges can be hermetically bridged in series with a conduit tocouple the first primary cartridge gas outlet to the second primarycartridge gas inlet.

Cassette Distribution Manifold Sub-Assembly

The base of a cassette can contain a cassette distribution manifold.This manifold interfaces the liquid module restrictor column, the firstprimary cartridge gas inlet, the second primary cartridge gas outlet andthe console room air pump inflow and NO gas outflow ports. In addition,a port is provided for the console to access the purge chamber.

The cassette distribution manifold can provide a gas-tight seal betweenthe first primary cartridge gas inlet as well as the second primarycartridge gas outlet. The cassette distribution manifold can contain twoschrader-like valves independent from the valves contained within theliquid module. These valves provide NO₂ gas escapement should thecassette be removed from the console or failure occurs to the outputshuttle seal. One schrader-like seal can be incorporated into the roomair pump inflow port and one schrader-like seal is incorporated into NOgas outflow port. Both valves are spring loaded normally closed andopened with the console probes. The cassette distribution manifold caninterface the console with probes that contain double (serviceable)O-ring seals. These seals should be compatible with high concentrationNO gas.

The base of the cassette can contain three ports as well DC electricalconnectors. A foil seal can be placed over the room air pump inflowport, the NO gas outflow port and the system purge port. The foilseal(s) are intended to be punctured by the console probes (notpealed-off) and must not interfere with the O-ring seals of the probeinterface.

Cassette/Console Interface

The cassette can be accessed through a cannula-like probe with doubleO-ring seals at each connection for redundancy in order to insure thatthere cannot be a leak at the connection: (1) the first connection canbe for the air pump input accessed through a schrader-like safety valve;(2) the second connection can be for the output of the second primarycartridge, again through a schrader-like safety valve for control anddistribution of the NO gas through the console for injection to thenasal cannula or the ventilator line.

The cassette can be accessed through a cannula-like probe with doubleO-ring seals at the purge port for access to the purge material from theconsole. The cassette can be accessed from the console for 12 or 24 VDCelectrical connections to manage the flexible heaters used to controlthe NO₂ gas flow by the console control system. The connection portsmust be NO₂ and air leak-tight to the internals of the console.

Purge Chamber

The purge chamber can contain a scrubbing material to the console systemplumbing exhaust. The potassium permanganate with sodium permanganatewith activated charcoal can be utilized. The purge chamber may be ventedto the atmosphere after the NO gas is neutralized by the medium or bedirected to a pressure relief valve. The scrubbing material used duringthe start-up and purge process to scrub any NOx before exhaust to theenvironment.

Cassette Housing and Assembly

The cassette housing can contain the above sub-assemblies into a singlecontainer. The assembly should be non-user accessible. This may includea welded assembly or a “special key” to open the cassette at themanufacturing site. Appropriate labeling as authorized by the regulatorybodies must be included on the cassette and associated packaging. Thetop of the cassette can contain a tamper resistant strip to isolate theactivation cam from the user to inhibit manual activation of the liquidmodule during cassette handling.

Cartridge

A cartridge is a system used to convert NO₂ gas generated from theliquid module to inhaled NO gas delivered to the patient and controlledby the console. The cartridge is housed in the cassette that interfacesthe console. To minimize risk two such cartridges, each sized to be ableto convert one complete N₂O₄ charge, and each from a differentmanufacture lot are included in the cassette. Referring to FIG. 5A, FIG.5A is a gross view of a cartridge with a cartridge housing 501 and acomposite cap 502 secured to inlet end of the composite. Referring toFIG. 5B, FIG. 5B depicts a cross-section of FIG. 5A with a cap 503secured to an inlet having an end 504.

A composite is utilized to provide a porous rigid matrix consisting of ablend of silica gel and high density polyethylene (HDPE). The HDPE isthe binding material utilized to construct the rigid matrix. A sinteringprocess is utilized to secure the structure. The composite can bedesigned to have as high a percentage (can be between 40% and 85%) ofsilica gel as possible and still maintain mechanical integrity. Toachieve a composite that is uniform, the HDPE particle size distributioncan be chosen to be similar to that of the silica gel. To achieve this,the HDPE particles are sieved using a pre-determined mesh size, and theparticles that fall through the mesh are used in the process. In orderto get an increased amount of silica gel in the composite, a HDPE with ahigh melt flow is utilized. This allows for the HDPE to melt togethermore, and therefore providing a matrix that allows for more silica gel,albeit with a higher pressure drop. Once the HDPE and silica gel areadded to each other, they are mixed for a certain amount of time thatallows for adequate mixing.

A putative mechanism poses that the ascorbic acid is associated to thesilica through water mediated bonds. Water is necessary for the reactionto occur at a sufficient level to achieve a quantitative conversion ofNO₂ to NO. Based on the pore size tests of various silicas, a pore sizeof about 40-80 A, about the size of one to two ascorbic acid molecules,is necessary for maximum conversion capability. It appears that theascorbic acid is being bound on the surface of the silica in a way thatactivates it for conversion. This may be due to the nucleophilicity ofthe silica mediated by the bound water to enhance the ability ofascorbic acid to give up protons to NO₂, creating a rapid, concertedreaction to form NO. Sodium ascorbate does not convert NO₂ to NO, whichsupports the putative concerted reaction mechanism.

Water also enhances the ability of silica-bound NO₂ to move through thecartridge to ascorbic acid, thus increasing the NO output and increasingcartridge efficiency. This water would not be directly associated withthe ascorbic acid, but just the silica. Too much water in the input gasflow to the cartridge, identified by active condensation on the surfaceof the cartridge, can dissolve and wash away ascorbic acid, providinggas paths that have poor to no conversion ability and results in earlycartridge failure. Also, too much water on an anaerobically sealedcartridge over time, results in an anaerobic degradation of ascorbicacid which generates CO₂ and decreases the conversion capacity of thecartridge. So, the stored cartridges should have moisture, yet should bereasonably dry to maintain shelf-life, though work is ongoing tooptimize the storage by achieving a balance between too moist and toodry.

Primary Cartridge Modules

The primary cartridge can be the specially designed composite processedwith ascorbic acid. A requirement of a single primary cartridge is thatit can be able to convert one complete load from a liquid vial. Forsafety and redundancy, two primary cartridges can be used, and they bothcan come from different production lots.

Composite Assembly

A composite is a porous rigid matrix consisting of a blend of silica geland high density polyethylene (HDPE). The silica gel is intended toprovide the surface structure to capture the Ascorbic Acid and moistureto initiate the conversion of NO₂ gas to NO gas. The HDPE is the bindingmaterial utilized to construct the rigid matrix. A sintering process isutilized to secure the structure. The composite is bonded to an upperand lower HDPE end caps and prepared for shipping/storage. The compositecan be designed to have as high a percentage (70% to 85%) of silica gelas possible and still maintain mechanical integrity.

Ascorbic Acid Derivatization

The ascorbic acid solution is made using ascorbic acid and purifiedwater. The concentration is determined using a weight to volume (w/v)method. The assembled composite is actively flushed with the solution ofa predetermined concentration. (It should be noted: After the ascorbicacid solution is made, it can be used in 48 hours, and the solution canbe discarded no later than 48 hours after manufacture in an acceptablemanner. This is to prevent a large portion of the ascorbic acid tobecome dehydroxyascorbic acid, rendering it useless as an oxidizingagent). The composites are then dried to a controlled dew point.

Water has a necessary role in the function of the GeNO cartridge. Pastwork showed that the cartridge requires the ascorbic acid to beassociated with a solid surface, with silica being the most efficient,and water is necessary for the cartridge to function. The ascorbic acidmust be distributed evenly over the silica and this is achieved throughdissolving it and applying it to the silica as a solution. The mix isthen dried evenly to achieve a uniform distribution which does notprovide preferred gas paths through the coated silica. The silica is ofa size that it packs well and has sufficient separation between thebeads to allow ample gas flow (˜200-500 μm), yet forces the gas to havemaximum access to the ascorbic acid bound to the silica.

Liquid Module

Referring to FIG. 6, a liquid module utilized is a sub-assembly used tostore, and contain a glass ampoule 601 with liquid N₂O₄. The glassampoule 601 is carried by a shuttle 602 that translates linear androtational force to effect port closure at the distal or proximal endand effect ampoule breakage to release the ampule contents. Ampoulebreakage interference feature 603. Flex heaters 604 wrap around theliquid module and restrictor column assemblies. “T”-fitting 605 is usedto deliver concentrated NO₂ gas to flowing room air 606 across arestrictor 607 distal end. The flow restrictor 607 is a microbore glasstubing for the NO₂ emerging from the liquid module. A slow leak valve608 to inerting chamber to neutralize NO₂ gas. Luer feature is for R&Duse to determine the acceptable leak rate for design integration. Camactivation means 609 for shuttle movement can be positioned at thedistal end of the liquid module.

Upon system activation (glass ampoule breakage), the liquid module cancontain NO₂ and N₂O₄ gas generated when the container is heated toconvert the liquid to a gas. The liquid module contains an internalmechanism to divert gas flow to either an inerting chamber or to thepatient delivery plumbing of the console. It is this NO₂ gas generatedfrom the liquid module that upon conversion to NO gas is delivered tothe patient and controlled by the console. The liquid module is housedin the cassette that interfaces the console.

A liquid module can contain a sealed vial of N₂O₄ until activation ofthe system by the user. A liquid vial can contain a measure quantity ofliquid N₂O₄ in a hermetically sealed glass vessel. A liquid module canprovide a safe transport means for the chemical and chemicalcompatibility with the liquid N₂O₄ and NO₂ gas. A liquid module canprovide a means to close the inerting chamber path, open the system flowpath and break the ampule upon user demand. Provide a means to open theinerting chamber path and close the system flow path should Cassette beremoved from the Console. A liquid module can provide a means to deliverμg of NO₂ in a controlled manner by temperature regulation (from theconsole controls) of the Liquid Module and Restrictor Assembly usingflexible heating elements wrapped about the assemblies.

A liquid module can provide a means to deliver concentrated NO₂ gas tosupplied room air to dilute the NO₂ gas before delivery to theconversion cartridges.

Mechanical Activation of the Liquid Module

A liquid vessel can contain the shuttle mechanism that orchestrates thegas delivery within the system. The vessel contains a shuttle feature, aheating feature and a regulator/restrictor feature.

Shuttle Feature has Multiple Performance Requirements:

A glass vial can be contained within a shuttle for shipment and storage.The shuttle can contain a feature that contains the glass vial shardsfrom passing through the ports at either end of the liquid vessel. Theshuttle can have two positions derived through shuttle rotation: shuttlecan seal at either end of the liquid vessel. In one position, a gas flowcan be directed to the inerting chamber and sealed to patient flow path.In another position, a gas flow is directed to the patient flow path andsealed to the inerting chamber. There can be a position where both flowpaths are sealed from gas flow by single seals at either end of theshuttle but occurs at an instance in time during the shuttle rotation.

The system can be activated by rotating the shuttle to engage a featurethat can result in glass vial breakage and expose the liquid N₂O₄ to theliquid vessel. The shuttle can be locked at the end of travel. Thesystem should be configured that the mechanism closes the patient flowpath and opens the inerting chamber before allowing for removal of thecassette. The Glass Vial should maintain structural integrity duringproduct shipment and storage.

Heating Feature has Multiple Performance Requirements:

Wrapped about the outside of the liquid vessel can be a flexible heaterthat is utilized to increase or decrease the gas output of the NO₂ gasfor patient delivery. The temperature is controlled by software withinthe console. Wrapped about the outside of the flow Regulator feature canbe another flexible heater that is utilized to increase or decrease thegas output of the NO₂ gas for patient delivery. The temperature iscontrolled by software within the console.

Regulator/Restrictor Feature has Multiple Performance Requirements:

The regulator/restrictor is utilized in conjunction with the heaters, tocontrol the output gas delivered to the patient delivery gas flowstream. The liquid module can create an internal pressure≥2X thepressure in the air inflow mixing T-fitting.

Access to Inerting Chamber

The liquid module inerting chamber is coupled to the liquid vesselthrough a controlled leak valve. The valve is intended to control therate gas flow to the inerting material to minimize chemical reactionheat build-up that occurs as the NO₂ gas is neutralized.

The shipping and shut-off design/configuration position of the shuttlecan expose the Liquid Vessel chamber to the Inerting port and seal-offthe patient delivery port. Should glass breakage occur during productshipment, it is intended for the device to contain the hazardous NO2 gasby diverting it to the Inerting Chamber to neutralize the gas.

A Supply Subassembly

A supply subassembly of a nitric oxide delivery system can include acassette module, cartridge(s) and a liquid module. The system includes acontrol subassembly, a NO supply subassembly, and a sample sensorsubassembly. The control subassembly includes a computer system withsmall integral display, a battery for backup, an application specificPCB (heater control, solenoid control, switches, battery charger,analogue input, etc.), and a computer memory storage system. The NOsupply subassembly includes 1) a cassette including a heated vessel,primary cartridges, an inerting material, a purge scrubber, arestrictor, and a housing, 2) an injector flow module including a flowsensor, pumps, a flow restrictor, a scrubber, a particulate filter, anair dump back pressure regulator, and a pump backup solenoid, and 3) aNO source control including a proportional valve, a purge solenoid, apurge flow sensor, a purge back pressure regulator, and Hi-C NO sensor.The sample sensor subassembly includes a sample/calibration solenoid, apermapure drier, a sample flow module (including a flow meter, a flowrestrictor, and a pump), a water trap (external) and a pressuretransducer, a sensor subassembly (NO, NO₂ and oxygen sensors and sensorcontrol PCB, and a NO_(x) scrubber.

Referring to FIG. 7, this shows the flow scheme of the supplysubassembly. The room air is introduced to a particulate filter and canflow into two pumps (FIG. 7, Pump (1) and Pump (2)). Pump (1) is capableof flows up to 1 L/min at 5 PSI or greater, which can satisfy allventilator and some cannula applications. Pump (2) can be used to supplydilution air to achieve the higher cannula flows when required. For theventilator application, flow from 0.2 to 1.0 L/min can be required.These pumps typically do not have this large, i.e. 5X, dynamic rangewithout stalling out at the lower flows, thus the need for Back PressureRegulator 1. Under typical ventilator operation, the proportional valve,Sol2 sets the output flow, which is also the flow measured by FlowSensor (1). If the pump is sets to the lowest acceptable flow, whichexceeds the desired output flow, the excess is automatically exhaustedthrough regulator (1) into the room. Since this in only air, it isacceptable to exhaust this gas. Since Pump (1) has been chosen toachieve flows up to 1 L/min for the ventilator application, and since attime flows as high as 4 L/min may be required for the cannulaapplication, Pump (2) has been added as a “dilution” pump. Pump (2) mostlikely could be identical to Pump (1) since Pump (1) is required tosupply 1 L/min at pressure of greater than 5 PSI, while Pump (2) isoperating at nominal atmospheric pressure, thus it may be able toachieve 3 L/min at nominal 0 PSIG.

Accumulator (1) along with a restrictor can be used to dampen out thepulsations from the diaphragm pump. It is desired to have a steady andnot pulsating flow through the rest of the system. Note that Restrictor1 must be significantly less restrictive than Restrictor 2. Accumulator2 and Restrictor 3 can be used to dampen the pulsations from thediaphragm Pump (2).

Flow Sensor (4) is used to determine the dilution flow from Pump (2)that mixes with the Acute output. The total flow to the patient is thesum of the flows of Flow Sensor (1) and (4). Based upon the flow setpoint the software can determine the actual ratio of the flows from Pump(1) and Pump (2). This is an optional pressure sensor. It would be usedto confirm that Back Pressure Regulator 1, when Sol1 is open, is setproperly. Under all conditions, i.e. Sol1 activated or not, it measuresthe pressure of the pump, which is a measure of the pump performance.Knowing the pump operational voltage, the output flow and pressure canbe used to determine if there is any degradation of the pump, and givean early warning signal to replace the pump before failure.

Other Exemplary Embodiments

An N₂O₄ liquid based system can be used to deliver inhaled nitric oxide(NO). The delivery system can be intended to be used in conjunctioneither with a ventilator or a cannula. The liquid N₂O₄ boils off as NO₂(gas), since in liquid form NO₂ can be present as the N₂O₄ dimer. TheNO₂ can then be converted into NO using at least one convertingcartridge. The amount of NO presented to the patient can be varied bychanging the temperature of the N₂O₄ liquid reservoir, and thus thevapor pressure above the liquid, by the choice and temperature of therestrictor column, and by the settings of the scrubbed by-pass air flowif used. The NO concentration can be controlled via a feedback loop fromthe NO sensor monitoring the NO in the patient ventilator or cannulaline, just prior to the patient. This feedback loop can control theliquid and restrictor temperatures and the flow through the scrubbedby-pass system if the scrubbed by-pass system is active. A console willprovide NO concentrations from 1 to 40 PPM with ventilator flows between2 to 20 LPM for the ventilator application, and 10 to 80 PPM at outputflows of 0.5 to 4 LPM for the cannula application. A secondary NO₂ to NOconverting cartridge will be placed just before the patient. Thissecondary cartridge will remove any residual NO2 that may have beenformed in the delivery gas plumbing, thus ensuring that the ventilationor cannula gas presented to the patient has an NO₂ concentration ofvirtually zero.

Referring to FIG. 8, in one embodiment, a system (such as the GeNOsylAcute DS) can be comprised of 1) a primary console, 2) an identical,fully-functional backup console (required for the ventilator mode,optional for the cannula modes), 3) one cassette per console, and 4)external tubing and accessories. A system can include both the primaryconsole and the backup console. Failure of a system can include theinability of both the primary and backup consoles to deliver NO at thedesired set point.

Referring to FIG. 9, the figure shows an exemplary GeNOsyl Acute DSConsole with Cassette door OPEN and displaying 3-position activationlever.

A system can be a hospital-based nitric oxide (NO) delivery system thatcan deliver controlled doses of inhaled NO for diagnostic or therapeuticpurposes to a patient in conjunction with a ventilator system or directthrough a nasal cannula.

A delivery system can be used in several configurations. The ventilatorconfiguration can be used with a face mask in conjunction with aventilator for therapeutic use. The cannula configuration can be usedwith a nasal cannula or a face mask for both therapeutic and diagnosticapplications. A console can includes a single cassette, which canincorporate liquid N₂O₄, and a pair of NO₂ to NO converting cartridges(primary cartridge).

Upon initiation of the console, the liquid N₂O₄ can be heated and canconvert to NO_(2(gas)). The NO₂ can then be converted into NO using NO₂to NO converting cartridges and delivered to the patient in conjunctionwith a ventilator system or direct through a nasal cannula or face mask.The amount of NO presented to the patient can be varied by changing thetemperature of the N₂O₄ liquid module. The NO concentration at thepatient can be controlled via a feedback loop from an NO electrochemicalsensor, which can monitor the NO in the patient ventilator line orcannula line. The NO sensor output can be compared to the demand NOconcentration (NO concentration set point chosen by the user) by thecontrol circuitry which in turn can adjust the liquid moduletemperature.

Referring to FIG. 10, the figure depicts an exemplary output performancecurve. NO concentration delivered to the patient can range from about0.1 PPM NO with a ventilator flow of 2 LPM to 20 PPM at 10 LPM (nominal,up to 40 PPM under extreme conditions with reduced Cassette lifetime).The system operates with an optional humidifier placed after acartridge, for example, a secondary cartridge. A secondary cartridge canconvert any residual NO₂, or NO₂ formed due to line conversion, tovirtually zero. A secondary cartridge can be placed before anyhumidifier so as to prevent condensation from forming in the cartridge.

GeNOsyl™ Acute DS Cannula System

The GeNOsyl™ Acute DS, may only provide a tiny fraction of the inputvolume of a breath, the rest being made up of room air (entrained air).The GeNOsyl™ Acute DS can control the concentration of the NO at thecannula. One advantage of the GeNOsyl™ Acute DS as compared to using agas tank may be that for the DS, both the flow and the concentration canbe varied, whereas when using a gas bottle only the flow rate can bevaried.

GeNOsyl™ Acute DS Ventilator System with Secondary Cartridge

For the GeNOsyl™ Acute DS both the output flow and the outputconcentration are variable. In order not to affect the ventilatorcontrols, the output flow of the GeNOsyl™ Acute DS can typically belimited to no more than about 10% of the total flow from the ventilator.Since the NO output of the console can be controlled by the temperature,and varying the temperature can change the mass of NO supplied perminute, it can be the temperature of the vessel that determines the massdelivered to the patient.

Cassette

When a cassette is inserted into a console and activated, for example,by breaking the cassette seals, the two parts of the cassette interactto control the dose of NO gas delivered to the patient. A cassette canbe a self-contained disposable product that can be inserted into aconsole (for example, the GeNOsyl Acute DS Console), which can beexternally coupled with a secondary cartridge to form a system, forexample, the Acute DS System.

Referring to FIG. 11, a cassette 1101 can include various modules thatproduce and convert the NO gas delivered to the patient. The cassetteand cartridges can be disposable modules that also provide user andenvironmental safety features and indicators. For example, a cassette1101 can be a self-contained disposable cassette with a viewing window1102, such as a color change inerting material viewing window forexample, that is configured to render the cartridge safe for disposal.

A cassette can include three discrete subassembly modules.

Liquid Module Assembly

Referring to FIG. 12, a cassette assembly can include a liquid moduleassembly 1203, a cartridge 1202, a cartridge bridge tubing 1201, and abase 1204. The liquid module assembly can contain and control theintegrity of the N₂O₄ holding vessel. A holding vessel (also referred toherein as a liquid vessel) can include one or more components forbreaking the glass seal and heating the N₂O₄ to activate the liquid,temperature controls to generate and maintain vessel pressure, and oneor more components for directing gas flow to either an inerting chamberor for delivery to the patient. A liquid module assembly can alsoinclude a NO₂ flow regulator to meter NO₂ from the holding vessel to theair stream used to carry the NO₂ through the gas circuit for conversioninto NO. To provide added safety from NO₂ exposure to the user in theevent of an accident or misuse, the N₂O₄ liquid chamber can be encasedin an inerting material. There can be also a hermetic barrier to containthe NO₂. The inerting material can initiate a color change indicator toalert the user that NO₂ has been discharged into the inerting chamber.

A liquid module assembly can be a sub-assembly used to store and containthe liquid N₂O₄. Upon system activation (glass ampoule breakage), theliquid module assembly will contain N₂O₄ and NO₂ gas generated when thecontainer can be heated to convert the liquid to a gas. The liquidmodule assembly can contain the internal mechanism to divert NO₂ gasflow to an integrated self-contained inerting chamber or directedtowards the flow restrictor for discharge to a cassettecircuit toconvert the NO₂ gas to NO. It can be this NO gas generated through acassette that can be delivered to the patient and controlled by aconsole.

The liquid module assembly can be housed in a cassette that interfaces aconsole. The liquid module assembly can incorporates temperaturecontrols that effectively control the NO2 gas pressure and a restrictorto control the rate of release of NO₂.

The liquid module assembly can operate in a manner to permit NO₂ gasflow to the primary cartridge OR to the inerting chamber. The mechanismmay make it impossible for both valve seals to be open simultaneously.

Referring to FIG. 13, a liquid vessel and restrictor assembly caninclude a glass ampoule 1307 with N₂O₄, metal liquid vessel 1308 withflex heater, shuttle 1307 and slow leak valve 1309 and seals, restrictorcolumn 1304, metal restrictor housing 1303, with flex heater & teefitting 1301, ferule 1302, an optional crush Teflon O-ring 1305, andheaters wrap the restrictor housing and liquid vessel (not shown).

Referring to FIG. 14, cartridge components include a primary cartridgehousing 1401, a composite inlet cap 1402, composite 1403 (silicagel/HDPE) and composite outlet cap 144.

NO₂ to NO Conversion Cartridges

A cassette can contain two independent NO₂ to NO conversion Cartridges.Referring to FIG. 15, each cartridge can include a cartridge outlet1501, a primary cartridge housing 1502, and a cartridge inlet 1503thereby forming a cartridge assembly, and can be capable of convertingthe entire capacity of the N₂O₄ liquid supply, with a >25% additionalcapacity. Two or more cartridges can be able to convert NO₂ to NO gas,with a safety factor of >150%. The system can be designed to operatesafely and effectively with one of the two cartridges being absent.Referring to FIG. 16, the cartridge can be mounted to a base 1602.

A primary can be contained within a cassette to convert NO₂ gas into NOgas. A cassette can contain one or more primary cartridges. If thecassette includes two or more cartridges, the cartridges can be inseries to provide double conversion redundancy before delivery of NO gasto the patient. This conversion can be accomplished through a reactionof NO₂ gas with a reducing agent included in the composite matrix. Gasflows through the coated composite in a torturous path created by thecomposite matrix to effect the conversion.

A composite can be a porous rigid matrix including a blend of silica geland high density polyethylene (HDPE). The HDPE can be the bindingmaterial utilized to construct the rigid matrix. A thermal sinteringprocess can be utilized to secure the structure.

Primary Cartridge Modules

A primary cartridge can be composite processed with ascorbic acid. Asingle primary cartridge can convert the entire fluid contents of thevial with >25% excess capacity. For safety and redundancy, two primarycartridges can be used.

Composite Assembly

A composite cartridge can be a porous rigid matrix. The porous matrixcan include a blend of silica gel and HDPE binder material. The silicagel provides the surface structure to capture the reducing agent, forexample, ascorbic acid, and moisture to initiate the conversion of NO₂gas to NO gas. The binding material can be utilized to construct therigid matrix.

The composite can be secured within the housing for stability inshipping/storage. The composite can be designed to have as high apercentage of silica gel as possible and still maintain mechanicalintegrity.

Ascorbic Acid Derivatization

The assembled composite can be actively flushed with a known solution ofascorbic acid dissolved in water. (Note: it can be important that oxygenbe excluded to minimize the conversion of ascorbic acid intodehydroxyascorbic acid.)

Water can play a role in the function of a cartridge. A reducing agentcan be distributed evenly over the porous matrix, and this can beachieved, for example, through dissolving it and applying it to theporous as a solution. The mix can then be dried evenly to achieve auniform distribution, which does not provide preferred gas paths throughthe matrix including. The porous matrix can be of a size that it packswell and has sufficient separation between the particles to allow amplegas flow, yet forces the gas to have maximum access to the reducingagent (e.g., ascorbic acid) bound to the porous matrix.

Cartridge Assembly

Upon completion, the treated composite assembly can be assembled to anouter housing, sealing it from the environment. A cartridge housing canhave an extremely low permeability to moisture and oxygen, or bepackaged such to minimize permeability to moisture and oxygen. Althoughthe cartridges can be packaged with the cassette, it can be important touse materials that provide adequate resistance to moisture and gas. Inone embodiment, the two cartridges in each cassette can be made fromdifferent manufacturing process lots for safety redundancy.

Cassette Housing Assembly

A cassette housing assembly can contain a structural base to which othercassette components can be mounted, including two Schrader valve-likeassemblies to provide independent gas flow, the outer housing with theinerting material, preferably color changing inerting material visible),and a tamper evident strip, which can shroud the cassette inlet andoutlet ports.

Referring to FIG. 17, the cassette base manifold can include aSchrader-like valve assembly 1701, an air IN access port 1702, and AirNO/OUT Access port 1703, and a foil seal 1704, which covers ports (notshown). The cassette base can provide access to the following systemfunctions:

-   -   Air_(IN) access through a Schrader-like valve assembly.    -   Air/NO_(OUT) access through a Schrader-like valve assembly.    -   Activation Rod access through small access port (non-accessible        activation by the user).    -   NO_(IN) gas purge/scrubber access.    -   NO_(OUT) gas purge/scrubber access.    -   Heater(s) and temperature sensor(s) electrical contacts exposed        for INACTIVE STANDBY mode (all passive components).    -   Tamper evident foil seals over access ports (except electrical        contacts).    -   Tamper evident foil seal breakage provides a mechanical        “lock-out” for Cassette reuse.

Referring to FIGS. 18A and 18B, these show the gas flow details of onecassette embodiment. FIG. 18A shows a gas flow bath showing the exitlocations on the base. FIG. 18B shows the exit locations from FIG. 18A.The numbers in the square box on the two figures refer to positions andare described below:

-   -   1 The gas flow intake from the console can be our own specially        designed Schrader valve. It can use a ball and a spring to seal,        and can be shown in more detail in FIG. 12.    -   2 The incoming air flow can be piped to a T fitting.    -   3 The incoming air can pass through the T fitting. Inside the T        fitting, the air can combine with NO2 coming from the liquid        vessel. The flow out of the liquid vessel can be controlled by        the upstream pressure in the vessel, which can be controlled by        the temperature of the liquid. The flow rate can be defined by        the pressure drop through the restrictor tube.    -   1 Air containing the NO2 can exits from the T fitting.    -   5 The air/NO2 mixture can leave the T fitting on its way to the        first ascorbic acid cartridge.    -   6 The air/NO2 mixture can enter the first ascorbic acid        cartridge. The flow can be forced to the outside of the        cartridge and it can exit out the center of the cartridge. The        cartridge itself can have a small taper to allow it to be molded        without the need for chemicals to release the cartridge from the        mold. The gas leaving the cartridge at the top of the figure may        now contain a mixture of air and NO. The gas can then enter the        second redundant cartridge.    -   7 The air/NO mixture can exit from the second cartridge.    -   8 The air/NO mixture can enter the second Schrader valve.    -   9 The air/NO mixture can exit from the cartridge.        The cassette design can assure that the NO₂ remains inside the        cassette and never leaves the cassette.

Referring to FIG. 19, this shows a cross-section of a Schrader-likevalve with a spring loaded ball 1802, normally closed. The ball isopened when inserted into the console. A cassette can be fullyintegrated, single use disposable and interfaces to a console. Acassette can be activated via the interface lever on the console whichcauses a console mechanism to engage the cassette, break the glassampoule and initiate NO delivery to the patient.

A cassette can provide adequate design safety features listed below tolimit NO₂ exposure to the equipment, user, patient or shipping carrier:

i Glass Ampoule

Volume of N₂O₄ contained in a cassette can be within the safeEPA/FDA/DOT limit.

ii Shuttle Seals

The N₂O₄ can be contained in a hermetically sealed glass ampoule thatcan be positioned in a plastic shuttle mechanism that (upon opening) canpermit NO₂ gas flow to either enter an inerting chamber or be directedout to the patient. The seals can all be doubly redundant.

iii Inerting Chamber

The cassette can be shipped with the glass ampoule exposed to theinerting material that would render the N₂O₄/NO₂ gas inactive should theglass ampoule break in shipment. The inerting material can undergo apermanent color change if exposed to N₂O₄. NO₂ liquid and the colorchange can become visible through the cassette window. This provides theuser with an indication that the cassette may no longer be functionaland should probably not be used.

iv Slow Leak Valve

In the event that the glass ampoule breaks prematurely, the gas flowrate into the inerting chamber can be controlled, for example, to managereaction temperature build-up and provide adequate time for the inertingreaction to occur.

v Schrader-Type Valves Sub-Assembly and Ports

All high concentration NO₂ gas plumbing can be contained within thecassette, thereby entirely eliminating environmental exposure to NO₂from a leak.

Both the air inflow and NO/Air gas outflow ports can provide back-upseals independent from the liquid vessel shuttle mechanism in case of anoutlet seal failure. These ports can have spring loaded automaticallyclosing Schrader valve.

vi Tamper-Evident Seal(s)

The base of the cassette can contains a foil seal covering the inflowand NO gas outflow Shrader valves. These seals may be punctured uponsystem activation to provide visual indications that the cassette hasbeen used as well as to provide a tamper evident seal from the userinadvertently challenging the Schrader seals.

vii Purge/Scrubbing Material

The cassette can also contain a purge/scrubbing material which can beused to scrub low level NO gas emerging from a console during priming ofthe system, and as a bypass during very low NO delivery concentrations.

viii Cassette Construction

The cassette housing can be capable of withstanding internal pressuresthat are 50% higher than can be generated during performance.

ix Shipping Packaging of the Cassette

The cassette packaging can be a clear container, such as a thermoformtray, that provides product integrity during shipping/transportationhandling as well as providing the user the ability to visualize theinerting chamber for color change (should the glass ampule break inshipment).

Referring to FIG. 20, this shows an exemplary cassette packaging.

A cassette can include two major systems: a) liquid module and b)conversion cartridges. The two systems can be independent but functionsymbiotically to convert liquid N₂O₄ to NO gas within the unitizedhousing. A cassette can interface to the console, which can provide thenecessary electronic, software and mechanical controls to control thedelivery of the desired NO/Air gas dose to the patient, delivered in thelow parts per million (PPM) concentration range.

The design can include a variety of safety features that provideenvironmental protection to the user. These safety features can beconsequential to the mechanism design but the intent of these safetyfeatures is generally to reconcile the potential harmful consequences ofunintended failures that could possibly occur.

Referring to FIG. 21, a cassette base assembly can include a cassettehousing 1801, a slow leak valve 1802 (optional design), 1 liquid vesselheater 1803, a liquid vessel 1804, glass ampoule 1805 with N₂O₄, ashuttle 1806, an ampoule crush feature 1807, Teflon crush washer 1808, asintered filter 1809, restrictor housing 1811, restrictor column 1812, arestrictor column heater 1813, ferule 1814, and tee fitting 1815.

Liquid Module

A cassette can provide containment for liquid N₂O₄. Liquid N₂O₄ can bethe primary component that when released and purified and its flowcontrolled, can result in known amounts of inhaled Nitric Oxide (NO).

The liquid N₂O₄ may be contained in variety of containers of which onemethod can be to dispense the liquid into an onion skin glass ampoulethat can then be hermetically sealed, for example, by means of a hotflame. The glass ampoule can resemble a capsule approximately 0.28inches in diameter and 1.25″ long with 0.0025″ wall thickness. Thediameter and wall thickness can be an industry standard glass ampouleand could have other shape features and dimensions. The N₂O₄ fill volumecan be less than 0.52 ml, which provides about one day's supply of NOgas during normal use.

A glass ampoule can include a number of features:

-   -   a) It can be clear, which can permit visualization in-process of        the fill volume;    -   b) It can provide a hermetically sealed environment for the        contents and can render it independent of environmental        conditions, such as temperature, humidity, etc.    -   c) It can provide a breakable container for on-demand        activation;        The design can provide mechanical and thermal features to expose        the contents of the glass ampoule to allow conversion of the        N₂O₄ liquid to NO₂ gas, and then regulate the NO₂ gas flow. This        can be accomplished within the liquid module.

The heart of the liquid module can be the liquid vessel and therestrictor housing assembly.

A liquid vessel can be cylindrical in shape with performance functionsat each end. Although shape may be not a controlling attribute, thepurpose can be to provide two distinct operating modes within thedevice: a) delivery of NO₂ gas out of the liquid vessel towards thepatient delivery conduits, or b) delivery of NO₂ gas to an inertingchamber for neutralization. To accomplish this, a shuttle mechanism canbe incorporated into the liquid vessel. The shuttle can move between twoend positions activated by a linkage from the console control. At oneend of a liquid vessel can be a port that leads to patient flowconduits. At the opposite end can be a port that leads to a hermeticallysealed inerting chamber contained within a cassette. In between, the tworesting positions of the shuttle through an interference feature thatupon initial activation compresses and fractures the glass ampoule (torelease the N₂O₄).

A shuttle can be housed within the liquid vessel, which can be made ofmetal, for example, stainless steel or titanium. A shuttle can contain afeature to safely hold and stabilize a glass ampoule. In its shippingposition to the customer, a shuttle can be positioned such that theinerting chamber port can be open to gas flow from the liquid vessel(which also results in the patient flow port being closed). Thiscondition can be for safety should the glass ampoule break in shipmentor handling, any N₂O₄/NO₂ that escapes from the broken glass will beexposed to the inerting material to neutralize it.

The activation of the system can only occur after the cassette can beplaced within the console. This can occur via an activation rod(controlled within the console) that can shift the position of theshuttle from inerting chamber open/patient flow port closed to patientflow port open/inerting chamber closed. Along the shuttle travel, theglass ampoule can contact an interference feature to break the glassampoule.

Heat can be applied to the liquid vessel for the purpose of vaporizingthe liquid N₂O4, and increasing its internal gas pressure so as to drivea known amount of NO₂ out of the vessel. The pressure can define thecontrolled amount of NO₂ discharged through the liquid module. Controlof the temperature can function as a pressure adjustment of the releaserate, for example, similar to a gas regulator does on a gas tank. Inthis design, flexible electrical resistance heater(s) can be wrappedabout the outside of the metal housing of the liquid vessel. Alternativeheating methods may be applied (rope heaters, cartridge heaters, orother types that will provide a controlled means of regulating liquidvessel temperature for the intended use duration). The temperaturecontrolled within the system can be regulated between 35° C. and 70° C.,for example, for the desired NO dose delivery to the patient.

-   -   a) A shuttle component can be cylindrical in shape with linear        valves at each end. A shuttle can provide a number of design        features:        -   i. A cradle that can safely contain the glass ampoule and            stabilize it during shipping and position the glass ampoule            for breaking during system activation.        -   ii. A shuttle can contain a pair of seals at each end to            seal off their respective ports when required.        -   iii. The seals at each end can be of different types. For            example, Luer-like tapered seal coupled with a radial seal.            These seals can be for redundancy and can interface their            respective seats in the liquid module assembly.        -   iv. A shuttle can incorporate a design feature whereby both            end ports are closed as the glass ampoule is breaking. This            can be accomplished by utilizing both radial seals on the            shuttle.        -   v. A shuttle can integrate a shield feature to shroud the            patient flow port from glass shards entering after            activation.        -   vi. A shuttle can be fabricated from FEP, PTFE, PFA, for            example, for contact chemical compatibility with N₂O₄.            Alternatively, a metal shuttle with compliant seal(s) may be            utilized. This may be stainless steel, titanium, aluminum,            brass, and others, for example.        -   vii. A shuttle can be connected to an activation rod, which            can include a spring loaded such that the shuttle is forced            to patient flow port closed/inerting chamber port open            position. This can be for added safety.        -   viii. The shuttle/liquid vessel clearances can be minimized            to reduce volume within the liquid vessel.    -   b) The liquid vessel component can be cylindrical in shape with        linear valve seats at each end. The liquid vessel can include a        number of design features:        -   i. Preferably constructed of metal (titanium, stainless            steel, aluminum, other), the liquid vessel can house and            contain the N₂O₄ and resultant NO₂ gas.        -   ii. A liquid vessel can contain an interference feature            along its inside wall that results in breaking the liquid            ampoule as it passes. (Note: this interference feature can            be a relative feature that could have also been included            within or on the shuttle.)        -   iii. A liquid vessel can contain a valve seat that            interfaces the shuttle seals to the inerting chamber.        -   iv. The exterior surface of a liquid vessel can be wrapped            with a flexible heater (controlled by the console).        -   v. The exterior surface of the liquid vessel can be            surrounded by the inerting material (soda lime) contained in            a plastic (polycarbonate, HDPE, ABS, etc.) material, again            for safety. Alternatively, this chamber may be metal should            there be concerns for a “take home” version be considered            e.g., could the “dog eat it”). The inerting chamber may be            placed anywhere contiguous with the liquid vessel discharge            port.        -   vi. A liquid vessel can contain a slow leak valve for NO₂            discharge into the inerting material. Alternatively, a slow            leak valve may be positioned on the shuttle.        -   vii. A liquid vessel, if a separate component, can be            affixed to the restrictor housing. A shuttle seat on the            patient flow port may be contained in either component.    -   c) A slow leak valve can be a laser drilled element (ruby,        stainless steel, titanium, etc.) component. A slow leak valve        can provide a controlled release of NO₂ gas from the liquid        vessel. The valve can be necessary during the discharge of NO₂        as the inerting chemical reaction forms a nitrate, and the        reaction can be exothermic. Too rapid of a discharge could        overheat the surrounding inerting material plastic surfaces. So        as not to compromise the structural integrity of these surfaces,        the NO₂ can be metered out so as to result in the discharge of        the entire N₂O₄ converted contents within 10 minutes.        -   i. A slow leak valve can have a controlled orifice of            approximately 0.005 to 0.030″.        -   ii. The diameter to ID length are functionally related to            control NO₂ discharge rate. Effectively, the larger the            diameter of the orifice, the longer the lumen, so as to            create a pressure drop to slow the NO₂ release.

Referring to FIG. 22, this depicts an exemplary shuttle mechanism.Initial position (shipping): inerting OPEN and patient flow CLOSED,glass ampoule intact. Neutralizer position is to the left and thepatient position with the glass restrictor is to the right.

Referring to FIG. 23, this depicts the shuttle mechanism with bothvalves closed—the glass ampoule has been broken and the brown liquidN₂O₄ has spilled out of the glass. Referring to FIG. 24, this depictsthe shuttle mechanism with Patient Flow Seal OPEN (right) & InertingSeal (left) CLOSED.

Referring to FIG. 25, this depicts the shuttle mechanism with the returnposition for cassette removal (same as initial shuttle position).

Referring to FIG. 26, a shuttle mechanism can include a liquidvessel/inerting chamber 2601, a slow leak valve 2602 (as an alternativedesign), an inerting seal seat 2603, shuttle inerting seals 2604 andLuer-like seal, a radial seal 2605, shuttle 2606, glass ampoule 2607 andN₂O₄, and a liquid vessel 2608.

Reaction Residence Time & Temperature

A restrictor housing can be an assembly comprising: a controlled orificelumen and length, a sintered filter, a ferule to connect the controlledorifice column to the restrictor housing, a tee connector and attachingmeans to hermetically join the restrictor housing to the liquid vessel.

The restrictor housing can provide an assembly structure used to controldelivery of NO₂ gas into an air steam (provided from the console). TheNO₂ gas can mix with the air on its path to the conversion cartridge(s).

Heat can be applied to the restrictor housing (controlled by theconsole) to maintain a gas temperature 5° C. to 20° C. above the liquidvessel temperature to inhibit condensation from forming and plugging thecontrolled orifice column.

The restrictor housing can include a number of components:

-   -   a) A restrictor column can be a static flow regulator that        discharges NO₂ gas conditional upon the inlet pressure created        in the liquid vessel. The pressure drop across the restrictor        column can be a function of lumen diameter and lumen length.        -   i. A restrictor column can manage a lumen diameter from            0.010 μm to 0.030 μm and a length from 1 cm to 4 cm.        -   ii. A glass column can be extruded coated with a PTFE outer            sleeve to protect the glass from handling damage and            assembly compliance.        -   iii. A restrictor column can be constructed of Type 1 Glass            (preferred), but other restrictor materials may be utilized            such as stainless steel, ruby, etc.        -   iv. A restrictor column can be affixed to the restrictor            housing utilizing a compressible ferule made from FEP, PTFE            or PFA, for example.        -   v. The column can be or include a fine bore quartz GC tubing            that has been coated with Teflon instead of polyimide.            Alternatively, a tiny orifice could be used that has the            same pressure drop as the GC column. The advantage of using            the relatively long column can be that the bore size can be            large enough to minimize clogging

Referring to FIG. 27, an exemplary patient flow port liquidvessel/restrictor housing assembly is shown. Such an assembly caninclude a glass ampoule 2701, a liquid vessel 2702, a Teflon crushwasher 2703, a glass shroud 2704, a liquid vessel fluid reservoir 2705,shuttle patient flow seals such as a radial seal 2706, and a Luer likeseal 2707, a patient flow seal seat 2708, a liquid vessel/restrictorhousing joining means 2709, restrictor housing 2710, sintered filter2711, and restrictor column 2712.

-   -   b) A restrictor housing can be a component, preferably metal,        with the following features:        -   i. A restrictor housing contains a lumen for assembling the            restrictor column and securing ferule.        -   ii. An alternative restrictor housing can incorporate a            metal tube structure about the restrictor column which can            be placed within the restrictor housing.        -   iii. A restrictor housing can contain a flexible heater            positioned on the outer cylindrical surface concentrated            near the gas discharge end to maintain the A temperature            between the liquid vessel and the restrictor column            discharge.        -   iv. A restrictor housing can be fabricated from metal.            Titanium, stainless steel or aluminum are preferred            materials.

Referring to FIG. 28, a restrictor housing tee fitting assembly caninclude inerting material 2801, a restrictor column 2802, a restrictorhousing 2803, a ferule 2804, a locking screw 2805, a NO₂ discharge 2806from the restrictor column, base 2807, tee fitting 2808, air inlet 2809and air/NO₂ outlet 2810.

-   -   c) A restrictor housing can contain a feature to affix a        restrictor filter up-stream from the restrictor column;        -   vi. A restrictor filter can be constructed of sintered            titanium without a binder. It can also be made from            stainless steel. It can also be coated with SiO2 to prevent            reaction on its large surface area.        -   vii. A restrictor filter can be press fitted into the            restrictor housing or intermediate metal tube.

Other Liquid Module Components can be included in the assembly. Thesecan include the inerting/purge chambers, inerting material, inertingchamber cap, purge/scrubber material, filler caps, and activation rodassembly.

Referring to FIG. 29, a liquid module housing and base housing caninclude inerting material surrounding a liquid vessel/restrictorassembly and scrubbing material. Specifically, it can include chamberfill ports 2901, inerting chamber 2902 to be filled with soda lime,liquid module housing (chambers) 2903, scrubbing (purge) chamber 2904 tobe filled with permanganate and a cartridge stabilizer 2905.

Referring to FIG. 30, a cassette cross-section through the inertingchamber and purge chamber is depicted. This includes ashuttle/activation rod coupling 3001, a purge chamber 3002, an inertingchamber 3003, liquid vessel 3004, restrictor housing 3005, and shuttleactivation rod 3006.

Referring to FIG. 31, a cassette assembly is shown. This includes acartridge bridge 3101, cartridges 3102, liquid module 3103 (with liquidvessel/restrictor assembly, inerting chamber and purge chamber), andbase 3104.

-   -   a) The inerting/purge chamber housing can be a polycarbonate        structure to house the inerting material/liquid        vessel/restrictor housing assembly and the purge/scrubbing        material can be unique compartments. An inerting/purge chamber        housing can have a number of design features:        -   i. An inerting chamber can completely house and encapsulate            the liquid module assembly with the inerting material;        -   ii. An inerting chamber can provide a visual indication if            the color change inerting material has changed color            resulting from NO₂ exposure;        -   iii. An inerting chamber can contain an inerting chamber cap            to which the restrictor housing can be connected and permit            passage of the heater wires and temperature sensors (one            with each heater). This cap can be sealed to result in a            hermetically sealed chamber.        -   iv. A purge/scrubber chamber can provide an independent            housing structure for the purge/scrubbing material used for            console exhaust.    -   b) An inerting material can be a blend of two materials. One        material can provide effective NO₂ neutralization while the        other material can exhibit a permanent color change when exposed        to NO₂.        -   i. A primary inerting material can be soda lime (70-90% of            mix).        -   ii. A permanent color change inerting material can be a            different formulation of soda lime (balance of mix).    -   c) A purge/scrubber material can be utilized to regulate the NO        concentration delivered to the patient. In situations where the        liquid module output may need to be reduced quickly (i.e., rapid        temperature decrease), excess NO may be diverted to the Scrubber        Material to neutralize it prior to environmental discharge. The        material can oxidize NO to form NO₂. The substrate can absorb        the NO₂.        -   i. A purge/scrubber material can be potassium permanganate            on a substrate, such as a molecular sieve.        -   ii. An additional component of activated charcoal may be            considered, or soda lime.    -   d) The activation rod assembly can provide a spring loaded,        normally closed patient flow port seal and can drive the shuttle        one direction to break the glass ampoule and close the inerting        chamber seal/open the patient flow port seal.        -   i. An activation rod assembly can be actuated by a feature            within the console and can be tied to the lever activation            handle.        -   ii. An activation rod can be coupled to the shuttle.            Conversion Cartridges

NO₂ gas can be carried with room air that can be pumped into the liquidmodule tee (or “T”) fitting at a flow rate of up to one liter perminute. The NO₂/Air mixture flows to the inlet of a first primarycartridge.

Referring to FIG. 32, a cross-section of a cassette through cartridges3201 is depicted. With the cartridges in the cassette, gas flow isoutside to inside.

A primary cartridge can contain a reducing agent included with a matrix,for example, ascorbic acid on silica gel which can react with NO₂ toform NO gas as the flow stream mixture crosses the cartridge wall.

A cartridge can include a number of components: a composite (which canbe a matrix), a composite inlet cap, a composite outlet cap, a compositehousing, a reducing agent (e.g., ascorbic acid coating), an inletfitting with tubing and an outlet fitting with tubing.

Two cartridges can be placed in series post-restrictor column. Bridgingfrom one subassembly to the next can utilize polyethylene tubing andbarbed fittings, for example.

Referring to FIG. 33, a cross-section of a cassette is shown. Thisdepicts an inerting chamber 3301, liquid vessel with glass ampoule 3302,cartridges 3303, and a purge chamber 3304.

-   -   a) A primary cartridge composite can be a matrix, for example, a        blend of silica gel and HDPE.        -   i. A primary composite can be a blend of 45% to 85% silica            gel to HDPE.        -   ii. A primary composite can be essentially cylindrical,            having an outside surface and an inside surface where            gas/air will flow from outside to inside (preferred) but            also works well with flow from inside to outside.        -   iii. An HDPE can be utilized as a binder to produce a rigid            composite structure. Alternatively, loosely packed silica            gel may also be utilized        -   iv. The percent of a reducing agent (e.g., ascorbic acid)            applied to a composite can be between 10% and 40%.    -   b) A primary composite can be affixed to an inlet cap to direct        gas/air flow through the side wall of a cartridge.        -   i. An inlet cap can be a HDPE component        -   ii. A design feature within an inlet cap can be a locating            feature to pilot into the housing inlet port to provide            stabilization for the cartridge during shipment, to            effectively have both ends of the composite secured.    -   c) A primary composite can be affixed to an outlet cap that        flows NO gas from inside of the composite to discharge to the        next subassembly.        -   i. An outlet cap can be a HDPE component        -   ii. An outlet cap can be affixed to the outer cartridge            housing port to provide a hermetic enclosure for a            cartridge.    -   d) A primary cartridge housing can be the outer structure about        the coated composite. These housings can provide physical        protection to the composite during process storage, can provide        a moisture barrier from the absorption of water during storage        and can provide an oxygen barrier from permeation during        storage.        -   i. A housing can be fabricated of HDPE.        -   ii. A composite can require a certain pressure (up to 5 psi)            to drive the NO₂ or NO through the composite wall. A primary            cartridge housing can retain that pressure permitting gas            flow through the cartridge.    -   e) The tubing and fittings can provide a conduit to advance the        gas from one subassembly to another. Alternative methods and        mechanisms for attaching components to other components are well        known in the art and may include ultrasonic welding, spin        welding, induction welding and other means.

The liquid module may be constructed in a radial configuration much likea petcock with two open positions (one for inerting and one for patientflow). This may be cylindrical or spherical shaped but dual seals can beused to prevent leakage between the ports.

The breaking of the glass ampoule can be currently a linear motion. Aradial motion can also be utilized. This radial motion may contain a cammotion to radially and linearly occur simultaneously.

Other embodiments are within the scope of the following claims.

What is claimed is:
 1. A storage device of liquid nitrogen dioxidecomprising a vessel including an ampoule, the ampoule including liquidnitrogen dioxide, wherein the liquid nitrogen dioxide converts to nitricoxide when the ampoule is broken, a restrictor, wherein a proximal endof the restrictor is facing the ampoule and a distal end of therestrictor provides an exit for nitric oxide gas; a leak valve connectedto the ampoule; and a shuttle tube containing the ampoule.
 2. Thestorage device of claim 1, wherein the shuttle tube connects with therestrictor when a user breaks the ampoule.
 3. The storage device ofclaim 2, wherein the heater is activated when a user breaks the ampoule.4. The storage device of claim 1, further connected to a heater.
 5. Thestorage device of claim 1, further connected to an inert chamber throughthe leak valve.
 6. The storage device of claim 5, wherein the shuttlerotates to connect the ampoule either to the inert chamber or to therestrictor.
 7. The storage device of claim 1, further connected to amixing T-fitting.
 8. The storage device of claim 7, wherein an air flowsinto the mixing T-fitting.
 9. The storage device of claim 1, wherein thevolume of the storage device is not greater than 0.53 mL.
 10. Thestorage device of claim 1, wherein the storage is device is contained ina sealed housing.
 11. The storage device of claim 10, the sealed housingfurther comprises a first cartridge capable of converting nitrogendioxide gas to nitric oxide within the sealed housing, the firstcartridge comprising an inlet, a diverter, a body, an outlet, and aporous solid matrix including a reducing agent, the porous solid matrixbeing positioned within the first cartridge such that there is a spacebetween the body of the first cartridge and the porous solid matrix,wherein the porous solid matrix includes an open passage parallel to thelength of the body of the first cartridge, a second cartridge capable ofconverting nitrogen dioxide gas to nitric oxide, wherein an outlet ofthe first cartridge and an inlet of the second cartridge is connected,the second cartridge comprising an inlet, a diverter, a body, an outlet,and a porous solid matrix including a reducing agent, the porous solidmatrix being positioned within the first cartridge such that there is aspace between the body of the first cartridge and the porous solidmatrix, wherein the porous solid matrix includes an open passageparallel to the length of the body of the first cartridge; and aninerting chamber including an inerting material.
 12. The cassette ofclaim 11, wherein the space has a width, which is a distance between thesurface of the porous solid matrix to the receptacle, and the width ofthe space is variable along the length of the receptacle, and whereinthe inlet is configured to receive a gas flow, the diverter directs thegas flow to the space between the body and the porous solid matrix, andthe gas flow is fluidly communicated to the outlet through the poroussolid matrix to convert nitrogen dioxide in the gas flow into nitricoxide.
 13. The cassette of claim 12, wherein the width of the spacedecreases along a portion of the length of the receptacle.
 14. Thecassette of claim 12, wherein the width of the space increases along aportion of the length of the receptacle.
 15. The cassette of claim 14,wherein the width of the space increases along a portion of the lengthof the receptacle extending from the inlet to approximately the midpointof the receptacle, and the width of the space decreases along a portionof the length of the receptacle extending from the approximately themidpoint of the receptacle to the outlet.